This application claims the benefit of foreign priority under 35 U.S.C. xc2xa7119 of German patent application no. 10060809.4-43, filed on Dec. 7, 2000 the contents of which are incorporated by reference herein.
The present invention relates to substituted anthranilic acids. In one embodiment, the invention relates to the use of substituted anthranilic acids as a medicament or diagnostic, including a medicament comprising at least one substituted anthranilic acid, and a pharmaceutical combination preparation containing at least one sodium/hydrogen exchange (NHE) blocker and at least one substituted anthranilic acid.
The invention relates to anthranilic acids of the formula I 
in which:
R(1) is H, Cl, Br, I, CN, (C1-C8)-alkyl, (C3-C6)-cycloalkyl, unsubstituted phenyl, or substituted phenyl
where the substituted phenyl is substituted by 1-3 substituents chosen from F, Cl, (C1-C3)-alkyl, methoxy and xe2x80x94(CF2)axe2x80x94CF3; and
where a is zero, 1, 2 or 3;
R(2) is (C1-C8)-alkyl, xe2x80x94CbH2bxe2x80x94(C3-C6)-cycloalkyl, unsubstituted xe2x80x94CbH2bphenyl, substituted xe2x80x94CbH2b-phenyl, unsubstituted xe2x80x94CbH2b-pyridinyl, substituted xe2x80x94CbH2b-pyridinyl, unsubstituted xe2x80x94CbH2b-thiophenyl, substituted xe2x80x94CbH2b-thiophenyl, unsubstituted xe2x80x94CbH2b-furanyl, or substituted xe2x80x94CbH2b-furanyl
where the substituted xe2x80x94CbH2b-phenyl, the substituted xe2x80x94CbH2b-pyridinyl, the substituted xe2x80x94CbH2b-thiophenyl, and the substituted xe2x80x94CbH2b-furanyl are each independently substituted by 1-3 substituents chosen from F, Cl, CF3, (C1-C3)-alkyl, methoxy and xe2x80x94SO2NR(4)R(5);
where R(4) and R(5) independently of one another are H or (C1-C4)-alkyl, and
where b is zero, 1, 2, 3 or 4;
R(3) is unsubstituted xe2x80x94CdH2d-phenyl or substituted xe2x80x94CdH2d-phenyl,
where the substituted xe2x80x94CdH2d-phenyl is substituted by 1-3 substituents chosen from F, Cl, CF3, (C1-C3)-alkyl and methoxy; and
where d is 3 or 4;
and their pharmaceutically tolerable salts.
In one embodiment, the compounds of formula 1 are those in which:
R(1) is Cl, (C1-C4)-alkyl, unsubstituted phenyl, or substituted phenyl
where the substituted phenyl is substituted by 1-3 substituents chosen from F, Cl, CF3, (C1-C3)-alkyl and methoxy;
R(2) is (C1-C4)-alkyl, xe2x80x94CbH2b-cyclohexyl, unsubstituted xe2x80x94CbH2b-phenyl, substituted xe2x80x94CbH2b-phenyl, unsubstituted xe2x80x94CbH2b-pyridinyl, substituted xe2x80x94CbH2b-pyridinyl, unsubstituted xe2x80x94CbH2b-thiophenyl, substituted xe2x80x94CbH2b-thiophenyl, unsubstituted xe2x80x94CbH2b-furanyl, or substituted xe2x80x94CbH2b-furanyl
where the substituted xe2x80x94CbH2b-phenyl, the substituted xe2x80x94CbH2b-pyridinyl, the substituted xe2x80x94CbH2b-thiophenyl, and the substituted xe2x80x94CbH2b-furanyl are each independently substituted by 1-3 substituents chosen from F, Cl, CF3, (C1-C3)-alkyl, methoxy and xe2x80x94SO2NH2; and
where b is zero, 1 or 2;
R(3) is unsubstituted -n-C4H8-phenyl or substituted -n-C4H8-phenyl,
where the substituted -n-C4H8-phenyl is substituted by 1-3 substituents chosen from F, Cl, CF3, (C1-C3)-alkyl and methoxy;
and their pharmaceutically tolerable salts.
In another embodiment, the compounds of formula 1 are those in which:
R(1) is Cl, (C1-C4)-alkyl, unsubstituted phenyl or substituted phenyl,
where the substituted phenyl is substituted by 1-3 substituents chosen from F, Cl, CF3, (C1-C3)-alkyl and methoxy;
R(2) is (C1-C4)-alkyl, xe2x80x94CbH2b-cyclohexyl, unsubstituted xe2x80x94CbH2b-phenyl, substituted xe2x80x94CbH2b-phenyl, unsubstituted xe2x80x94CbH2b-pyridinyl, substituted xe2x80x94CbH2b-pyridinyl, unsubstituted xe2x80x94CbH2b-thiophenyl, substituted xe2x80x94CbH2b-thiophenyl, unsubstituted xe2x80x94CbH2b-furanyl, or substituted xe2x80x94CbH2b-furanyl
where the substituted xe2x80x94CbH2b-phenyl, the substituted xe2x80x94CbH2b-pyridinyl, the substituted xe2x80x94CbH2b-thiophenyl, and the substituted xe2x80x94CbH2b-furanyl are each independently substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, (C1-C3)-alkyl, methoxy or xe2x80x94SO2NH2; and
where b is 1;
R(3) is unsubstituted -n-C4H8-phenyl or substituted -n-C4H8-phenyl,
where the substituted -n-C4H8-phenyl is substituted by 1-3 substituents chosen from F, Cl, CF3, (C1-C3)-alkyl and methoxy;
and their pharmaceutically tolerable salts.
In one embodiment, the compound of formula 1 may be chosen from 4-chloro-5-(3-chloro-4-fluorobenzylsulfamoyl)-2-phenylbutylaminobenzoic acid, and its pharmaceutically tolerable salts.
In another embodiment, if one of the substituents R(1) to R(5) comprises one or more asymmetric centers, each asymmetric center may independently have either the S or R configuration. Thus, for example, compounds of the invention may be present as optical isomers, as diastereomers, as racemates and as mixtures thereof. Alkyl, as used herein, may be either a straight-chain alkyl group or branched alkyl group.
In one embodiment, compounds of the formula I may be synthesized by the person skilled in the art according to processes known from the literature, including but not limited to: 
Possible leaving groups, X2 (formula VI), which can be taken into consideration in the nucleophilic aromatic substitution reaction with amines III include, but are not limited to, fluorine and chlorine.
The introduction of some substituents in the 4 position of intermediate II (X1, for example, may be bromine, iodine or xe2x80x94Oxe2x80x94SO2CF3) may, in one embodiment, be carried out by methods of palladium-mediated cross-coupling, which are likewise known from the literature, of aryl halides or aryl triflates with, for example, organostannanes, organoboronic acids or organoboranes or organocopper or zinc compounds.
In general, anthranilic acids are weak acids which bind bases with formation of salts. Possible base addition products are all pharmacologically tolerable salts, for example, alkali metal salts, lysinates and tris(hydroxymethyl)methylamine salts.
In one embodiment, the compounds of formula I are substituted anthranilic acids.
A prominent representative of the anthranilic acid class is the furfuryl derivative furosemide, which is used as a diuretic in therapy. Furosemide inhibits the sodium/potassium/2chlorine cotransporter in the ascending branch of Henle""s loop in the kidney. 
DE 18 02 208 describes anthranilic acids which differ from the compounds of the present invention in that they carry an exclusively benzyl, furfuryl or thienyl substituents on R3 and have diuretic action. U.S. Pat. No. 3,565,920 also discloses anthranilic acids that differ from the compounds of the formula I in that they demonstrate a strong salidiuretic activity.
It was therefore surprising that the compounds according to the invention have no undesired and disadvantageous salidiuretic properties, but very good cardioprotective properties, for example in the case of oxygen deficiency symptoms. As a result of their pharmacological properties, the compounds, in one embodiment, are outstandingly suitable as cardioprotective pharmaceuticals for infarct prophylaxis and infarct treatment, and for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention may, for example, be used, as a result of inhibition of the cellular Na+/HCO3xe2x88x92 cotransporter (NBC), as pharmaceuticals for the treatment of all acute or chronic damage caused by ischemia or illnesses induced primarily or secondarily thereby. In one embodiment, this relates to their use as pharmaceuticals for surgical interventions, e.g. in organ transplantation, where the compounds can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and during the transfer to the recipient""s body.
The compounds may also be useful pharmaceuticals having a protective action when carrying out angioplastic surgical interventions, for example on the heart, and also on peripheral vessels. Moreover, the inventive compounds may reduce the formation or the extent of cardiac insufficiency after various insults.
In another embodiment, corresponding to their protective action against ischemically induced damage, the compounds may be suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the CNS, where they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, the compounds of the formula I according to the invention may likewise be suitable for the treatment of forms of shock, such as of allergic, cardiogenic, hypovolemic and bacterial shock.
In a further embodiment, the compounds of the formula I according to the invention may be distinguished by strong inhibitory action on the proliferation of cells, for example, fibroblast cell proliferation and proliferation of the vascular smooth muscle cells. The compounds of the formula I may therefore be suitable as therapeutics for illnesses in which cell proliferation represents a primary or secondary cause, and may therefore be used as antiatherosclerotics, agents against diabetic late complications, carcinomatous conditions, fibrotic conditions such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidneys, organ hypertrophies and hyperplasias, in particular in prostate hyperplasia or prostate hypertropy.
The invention, in one embodiment, relates to a combination of an NBC blocker of formula I with sodium/hydrogen exchange (NHE) inhibitors. In combined therapeutic administration, both classes of active compound surprisingly exhibit synergistic effects in the treatment of syndromes which are to be attributed to ischemic conditions and reperfusion effects. The combinations of an NBC inhibitor with an NHE blocker may thus be suitable for infarct and reinfarct prophylaxis and infarct treatment, and for the treatment of angina pectoris and the inhibition of ischemically induced cardiac arrhythmias, tachycardia and the formation and maintenance of ventricular fibrillation. The combination may also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage.
Because of their increased protective actions against pathological hypoxic and ischemic situations, the combinations according to the invention may be used, for example, as a result of increased inhibition of the Na+ influx into the cell, as pharmaceuticals for the treatment of acute or chronic damage caused by ischemia or illnesses induced primarily or secondarily thereby. This may relate to their use as pharmaceuticals for surgical interventions, e.g. in organ transplantation, where the combinations of an NHE inhibitor with a blocker of the noninactivating sodium channel may be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example even during their storage in physiological bath fluids, and during transfer to the recipient""s body.
The combinations of an NBC blocker of the formula I with NHE inhibitors may be useful pharmaceuticals having a protective action when carrying out angioplastic surgical interventions, for example on the heart, and on peripheral vessels. Corresponding to their protective action against ischemically induced damage, these combinations may also be suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the central nervous system, where they are suitable for the treatment of stroke or of cerebral edema. Moreover, the combinations according to the invention may likewise be suitable for the treatment of forms of shock, for example of allergic, cardiogenic, hypovolemic and bacterial shock.
It was thus, for example, surprisingly found that the combination of the NBC blocker 4-chloro-5-(3-chloro-4-fluorobenzylsulfamoyl)-2-phenylbutylaminobenzoic acid with the NHE inhibitor cariporide mesilate, 
which is described, for example, in U.S. Pat. No. 5,591,754, exhibited a greater than additive cardioprotective action in an ischemia/reperfusion model (isolated beating rat heart).
Pharmaceuticals which contain a compound of formula I may, for example, be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration, in one embodiment, may depend on the respective clinical picture of the condition. The compounds of formula I may also be used here on their own or together with pharmaceutical excipients, mainly both in veterinary and human medicine.
The person skilled in the art is familiar on the basis of his/her expert knowledge with excipients which are suitable for the desired pharmaceutical formulation. In addition to solvents, gel formers, suppository bases, tablet excipients, and other excipients, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or colorants.
For a form for oral administration, for example, the active compounds may be mixed with the additives suitable therefor, such as vehicles, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Inert carriers which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular cornstarch. In this case, preparation may, for example, take place both as dry and as moist granules. Suitable oily vehicles or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
For subcutaneous or intravenous administration, for example, the active compounds may be brought into solution, suspension or emulsion, if desired, using the substances customary therefor such as solubilizers, emulsifiers or further excipients. Possible solvents are, for example: water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents mentioned.
Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents.
If required, the formulation may also contain still other pharmaceutical excipients, such as surfactants, emulsifiers and stabilizers, and a propellant. In one embodiment, such a preparation may contain the active compound in a concentration of about 0.1 to about 10, in particular of approximately 0.3 to 3.0% by weight.
The dose of the active compound of formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; moreover also on the nature and severity of the illness to be treated and on the sex, age and weight and individual responsiveness of the mammal to be treated.
On average, the daily dose of a compound of the formula I, in one embodiment, in the case of a patient weighing approximately 75 kg is at least 0.001 mg active to kg of body weight (mg/kg), such as 0.01 mg/kg to 10 mg/kg, such as, for example, 1 mg/kg. In another embodiment, in the case of acute episodes of the illness, for example immediately after suffering a cardiac infarct, even higher and especially more frequent doses may also be necessary, e.g. up to 4 individual doses per day. In particular in the case of i.v. administration, for example in the case of an infarct patient in the intensive care unit, up to 200 mg per day may be necessary.
List of Abbreviations
Analytical System
HPLC 1 Agilent 1100
Method gradient: 10% ACN (0.1% TFA)/90% water (0.1% TFA) to
90% ACN (0.1% TFA)/10% water (0.1% TFA) in 7 min, 2.5 ml/min
Column: Altech RP18, 3 xcexcm, 7xc3x9735 mm
MS: Waters Mass Lynxxe2x80x94ESI-TOF, [Mxe2x88x92H+]xe2x88x92, 100% peak, if not stated otherwise
HPLC 2 Agilent 1100 LC/MSD
Method gradient: 5% ACN (0.05% TFA)/95% water (0.05% TFA) to
95% ACN (0.05% TFA)/5% water (0.05% TFA) in 4 min, flow 0.5 ml/min
Column: ESI, [M+H+]+, Merck Purospher RP18, 5 xcexcm, 2xc3x9755 mm
Stage 1: 1.0 eq. of the 2,4-bis-halo-5-chlorosulfonylbenzoic acid of the formula VI is dissolved or suspended in ethyl acetate (5 ml/mmol) and then treated with 5 eq. of amine of the formula V. After stirring for 17 hours at RT, the reaction mixture is acidified to pH 1 to 2 using 2N hydrochloric acid and extracted with EA. After drying over MgSO4, the solv. is evaporated and the crude product is employed in the next stage without further purification.
Stage 2: 1.0 eq. of the 2,4-bis-halo-5-sulfamoylbenzoic acid derivative of the formula IV is treated with 5 eq. of amine of the formula III and heated at 100xc2x0 C. for 24 hours. After cooling the reaction mixture, it is treated with 5N citric acid solution and extracted with EA. The organic phase is concentrated and the crude product obtained is purified by means of preparative HPLC (RP gel, eluent acetonitrile/water gradient).